Stability preformulation stage

Solution dosage forms offer several advantages, particularly the resolution of bioavailability problems, instant administration as injectable forms (though nonsolution forms are also given parenterally). At the preformulation stage, more important factors are the solubility (and any pH dependence) and stability of the new compound. 

Data considered to be important for suspensions at the preformulation stage include solubility, particle size and propensity for crystal growth and chemical stability. Furthermore, during development, it will be important to have knowledge of the viscosity of the vehicle to obtain information with respect to settling of the suspended particles, syringibility and physical stability (Akers et al. 1987). In a report on the preformulation information required for suspensions, Morefield et al. (1987) investigated the relationship between the critical volume fraction as a function of pH. They noted that it is usually desirable to maximize the volume fraction of solids in order to minimize the volume of the dose . 

A pilot production is at about a lOOx level in general, the full scale-batch and the technology transfer at this stage should comprise preformulation information, product development report, and product stability and analytical methods reports. This is the time to finalize the batch production documentation for the lOOx level. The objectives of prevalidation trials at this stage are to qualify and optimize the process in full-scale production equipment and facilities. 

In the early stage of preformulation, characterization of the drug molecule involves ionization constants and partition coefficient determinations, aqueous and nonaqueous kinetic and equilibrium solubility determination, pH solubility profile, chemical stability assessment, and salt and polymorph screening. Assessment of biopharmaceutics and toxicological screening are also essential... 

Early on in product development, the potential for the successful development of a solid oral dosage form is assessed, based on the physicochemical properties of the API (1). Prior to solid dosage form development, it is necessary to anticipate the physicochemical properties that can have a major influence on product manufacture and performance. The early development (preformulation and early formulation development) studies should focus on these properties so as to avoid problems at later stages of development. While the molecular properties dictate the intrinsic solubility and the chemical stability of the compound, by controlling the physical form of the compound and by modifying physical properties (e.g., particle size), the dissolution rate can be enhanced with the potential for improving bioavailability. This chapter will focus on physical properties including particle characteristics, and most importantly, the physical form (i.e., solid state) of the API. 

From the summary data of the preformulation studies, scientists should obtain potential leads based on stability conditions designed in order to consider them for further development. The next stage of development, which we call formulation, should take into account all the parameters that may achieve one or more stable formulations for marketability with acceptable industrial stability. 

With these limitations in mind, this chapter concentrates on the specific considerations which are fundamental to the development of pharmaceutical dosage forms designed for application to the skin. Many of the early pharmaceutical development stages for these dosage forms, such as preformulation and drug substance stability, are common to dosage forms designed for other routes of delivery. These have been fully discussed elsewhere in this volume and will not be discussed in depth here. 

Before process validation can be started, manufacturing equipment and control instruments, as well as the formulation, must be qualified. The formulation of a pharmaceutical product should be studied in detail and qualified at the development stage, i.e., before the application for the marketing authorization is submitted. This involves preformulation studies, studies on the compatibility of active ingredients and excipients, and of final drug product and packaging material, stability studies, etc. 

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